Synaptic histamine shapes the neurocomputational dynamics of human learning

Abstract

Histamine was the first canonical monoamine identified in the mammalian brain 1-6, yet arguably remains the least understood in its mechanistic contributions to human behaviour. Using a first-in-class causal probe (H3R inverse agonist pitolisant), we show how increased synaptic histamine shapes offline and online temporal-hippocampal dynamics, sustaining learning-related activity and polarising retrieval computations. At a broader level, elevated histamine adaptively shifts neurocomputational strategy under high cognitive load, while stabilising value updates during aversive reinforcement learning. These findings uncover a mechanistically grounded influence of this underexplored system on human neurocomputation, supporting its therapeutic potential in psychiatry.